N-aroyl sulfonamides

ABSTRACT

N-Aroylperfluoroalkanesulfonamides wherein the perfluoroalkane group is methyl or ethyl and the aryl group is phenyl, naphthyl, pyridyl, thienyl, furyl, or pyrazinyl, optionally substituted, and their pharmaceutically acceptable salts, are active anticonvulsant agents. Processes for the preparation of these compounds are described.

United States Patent Moore et al.

1 j Dec. 5, 1972 N-AROYL SULFONAMIDES Inventors: George G. I. Moore,White Bear Lake; Alvin C. Conway, North St. Paul, both of Minn.

Appl. No.: 816,038

US. Cl. .....260/465 D, 260/556 F, 260/294.8 F, 260/332.2 C, 260/347.2,260/250 R, 260/545 R, 424/304, 424/321, 424/263, 424/275, 424/285,424/250 Int. Cl ..C07c'143/74 Field of Search ..260/556 F, 465 D [56]References Cited UN lTED STATES PATENTS 2,732,398 1/1956 Brice et al...260/556 F 2,915,554 12/1959 Ahlbrecht et a1 ..260/556 F PrimaryExaminerHenry R. Jiles Assistant Examiner-S. D. Winters Attorney-Kinney,Alexander, Sell, Steldt & Delahunt [57] ABSTRACTN-Aroylperfluoroalkanesulfonamides wherein the perfluoroalkane group ismethyl or ethyl and the aryl group is phenyl, naphthyl, pyridyl,thienyl, furyl, or pyrazinyl, optionally substituted, and theirpharmaceutically acceptable salts, are active anticonvulsant agents.Processes for the preparation of these compounds are described.

15 Claims, N0 Drawings N-AROYL SULFONAMIDES BACKGROUND OF THEINVENTION 1. Field of the Invention 4 This invention relates toN-substituted perfluoroalkanesulfonamides and to compounds havinganticonvulsant activity.

2. Prior Art N-Substituted sulfonamides and N-substitutedperlluoroalkancsulfonamides wherein the fluoroalkane chain is four to 12carbon atoms are known to the art. US. Pat. No. 2,995,542 describedcompounds in which the nitrogen atom of the fluoroalkanesulfonamidogroup is substituted by a carbonyl carbon. However, the compoundsdescribed there are fluorocarbon acrylic-type sulfonamides. No priordisclosure of N-aroylperfluoroalkanesulfonamides or their physiologicalactivity is known.

SUMMARY OF THE INVENTION DETAILED DESCRIPTION OF THE INVENTION Thisinvention relatesto compounds of the formula Formula I wherein n iszero, one or two, Y is selected independently from the group consistingof lower alkyl, lower haloalkyl, lower alkoxy, phenyl, halogen, nitro,and cyano but Y may not occupy a position ortho to the carbonyl groupexcept when Y is fluorine, or when Ar is phenyl, n is 2 and Y ischlorine and not more than one chlorine atom is in the ortho position;Ar is phenyl, naphthyl, pyridyl, thienyl, furyl or pyrazinyl and R, isperfluoroalkyl of one or two carbon atoms; and pharmaceuticallyacceptable salts thereof.

The term lower when applied herein to alkyl, haloalkyl, alkoxy andalkylsulfonyl substituents signities the presence of one to four carbonatoms; substituents having one carbon atom are preferred, becausestarting materials for such compounds are generally more readilyavailable.

R, is preferably trifluoromethyl, since the compounds containing thisgroup have generally been somewhat more active as anticonvulsant agents.Compounds wherein R, contains as many as four carbon atoms are inactive.

When the substituent Y occupies a position ortho to the carbonyl groupof Formula I it has been observed that substituents other than fluorinegenerally result in reduced activity in the compounds of the presentinvention. No completely satisfactory theoretical explanation for thisobservation is known, although the steric bulk of the substituent isprobably involved. However, one exception to this observation is thecase of compounds having two chlorine atoms occupying positions on thearomatic ring, although both chlorine atoms may not be ortho.

The amido nitrogen of the compounds of Formula I bears a hydrogen whichis relatively acidic. It may be replaced by metal ions by neutralizatione.g., with a base or a salt of a weak acid to form salts of thecompound. Suitable metal ions which may be utilized are preferably thosewhich are pharmaceutically acceptable, for example sodium and potassium,when the compounds of the invention are to be used as anticonvulsants.Other pharmaceutically acceptable cations, which are well known to theart, may also be included in salts of the compounds of the invention.

The compounds of the invention are prepared conveniently by the reactionof an aroyl halide with a perfluoroalkanesulfonamide or its salt asshown in the following equation:

Equation I In this equation Y, n, Ar and R; are as defined above, M ishydrogen or a metal ion and X is halogen, preferably chlorine, since thearoyl chlorides are generally more conveniently available.

The aroyl halides or their precursor acids and theperfluoroalkanesulfonamides and their salts used to prepare thecompounds of this invention are known to the art, or are readilyprepared by methods known to the art. Thus, theperfluoroalkanesulfonamides can be prepared as described in U. S. Pat.No. 2,732,398; aroyl halides are readily prepared by treating aromaticacids or anhydride with thionyl chloride.

Aroyl anhydrides may be used in place of aroyl halides, although theyare generally not preferred.

It is preferred that the reaction be run in the presence of base,although base is not essential, and a non-reactive solvent is preferred.Conveniently, this solvent is acetone, but other solvents includingalkyl ketones, esters, monoand diglyme, benzene, alkanes, chlorinatedhydrocarbons and the like can be used. It is preferred that thesesolvents dissolve most of the reactants to facilitate homogeneousreaction. Bases which are suitable include salts of weak acids such assodium acetate and sodium carbonate and organic tertiary amines such astriethylamine and N,N-dimethylaniline. The reaction is preferably rununder anhydrous conditions, and when very reactive acyl halides areused, under an atmosphere of a'relatively inert gas such as nitrogen.Other equivalent procedures to obtain dry of an amide, or its salt, witha perfluoroalkanesulfonyl halide, as shown in the following equation Inthe equation above Y, n, Ar, R,, M and X are as defined previouslyhereinabove. However, this route is presently believed to be lessdesirable. Other routes such as the reaction of ketenes withperfluoroalkanesulfonamides are possible routes to the compounds of theinvention.

For general use as anticonvulsants, the compounds of the presentinvention are preferably administered orally. For oral administrationthey are preferably administered as salts of pharmaceutically acceptableca- The preferred anticonvulsant compounds of the present inventioninclude N-(Z-fluorobenzoyl)trifluoromethanesulfonamideN-benzoyltrifluoromethanesulfonamideN-(3-nitrobenzoyl)trifluoromethanesulfonamide N-(3-trifluoromethylbenzoyl )trifluoromethanesulfonamideN-(3-chlorobenzoyl)trifluorornethanesulfonamideN-(3-fluorobenzoyl)trifluoromethanesulfonamideN-(4-nitrobenzoyl)trifluoromethanesulfonamideN-(2,4-dichlorobenzoyl)trifluoromethanesulfonamideN-(4-chlorobenzoyl)trifluoromethanesulfonamide N-( 3-bromobenzoyl)trifluoromethanesulfonamideN-(4-fluorobenzoyl)trifiuoromethanesulfonamideN-(3,4-dichlorobenzoyl)trifluoromethanesulfonamide and the sodium saltsof the above compounds. The

ion as are well known to the art, and particularly as preparation anduse of these compounds for their ansodium salts. The compounds of thepresent invention are active as anticonvulsants, although it will beappreciated that some are more active than others.

The compounds of the invention are especially advantageous because theduration of their effect is quite long, often exceeding 48 hours. Thispermits longer intervals between doses, with no reduction ineffectiveness. Alternatively, the repeated administration of lower,acutely subeffective dosages has been demonstrated to result in ultimatecomplete effectiveness. Thus subeffective dosages have a cumulativeeffect.

The specific does amounts of the compounds of Formula I which are to beadministered will depend on several factors including the weight of thewarmblooded animal recipient and the route of administration employed.Generally, the compounds of this invention are effective in doses of 0.1to 20 milligrams per kilogram daily. The amounts can be given in singleor multiple doses, as required.

The compounds of Formula I or their pharmaceutically acceptable saltscan be suitably formulated in physiologically acceptable solutions andcarriers to make tablets, syrups, isotonic solutions, injectablesolutions, suppositories and other dosage forms.

In order to examine the efficacy of the compounds of the'presentinvention in the prevention or reduction in severity of convulsiveseizures, they were tested by two methods, electro-shock andchemically-induced shock. More specifically, antagonism of cornealsupramaximal electroshock and l,5-pentamethylene-tetrazole-inducedseizures was used as the test methods.

The supramaximal electroshock technique is described in detail byTornan, et al., Journal of Neurophysiology 9:231, 1946).

In order to obtain a correlation of the effectiveness of the protectionwith the lethal hazard, the dose (ED that protects 50 percent of theanimals at the time of peak anti-shock effect is calculated, and iscompared to the median lethal dose, LD A therapeutic index (T.I. LD50/EDis calculated. Several of the preferred compounds of the invention havebeen found to have a therapeutic index greater than 5.

The production of l,5-pentamethylenetetrazole-induced seizures isdescribed in detail by Everett and Richards, Journal of Pharmacology andExperimental Therapeutics 81, 402 I944).

ticonvulsant action appears to be the presently best known means forpracticing the invention.

Certain compounds of this invention also show activity as insecticides,antimicrobial agents, diuretics, herbicides and plant growth modifiers.The herbicidal and plant growth modifying activity was determined usingscreening tests against experimental plantings. The-compounds of thisinvention are useful as chemical intermediates.

The activity of these compounds is theorized to be the result ofinhibition of the enzyme carbonic an hydrase. This theory is supportedby positive results in a standard in vitro assay. Thus some of thecompounds of the invention can be expected to be useful in a similarfashion to known carbonic anhydrase inhibitors, for example asdiuretics, anti-glaucoma agents and in the facilitation ofacclimatization to higher altitudes. Certain plant growth modifiers areknown to be effective inhibitors of plant carbonic anhydrase.

In order to further illustrate the invention the following non-limitingexamples are provided. Melting points are uncorrected.

EXAMPLE 1 N-Acylfluoroalkanesulfonamides: Procedure, according toEquation I.

A mixture of fluoroalkanesulfonamide (0.1 mole), sodium carbonate (0.2mole) and acetone (about 200 ml.) is stirred one or more hours under anitrogen atmosphere. The co-reactant acid chloride (0.1 mole), dilutedwith a small amount of acetone, is added during one or more hours. Amild exotherrn is-sometimes observed. The reaction mixture is stirredunder nitrogen for one or more hours, the mixture is filtered and theacetone is removed in vacuo. The product is a sodium salt, usually solidbut sometimes a sticky gum. Dissolution in water, treatment withdecolorizing charcoal and filtration may be used to partially purify theproduct. The product is reisolated by evaporation as the sodium salt, oracidification of the filtrate may be used to obtain the product compoundof Formula I. Some of these compounds of Formula I have an appreciablewater solubility. Recrystallization of compounds is usually carried outfrom trichloroethylene, or mixtures of aromatic and aliphatichydro-carbons such as benzenehexane. Sublimation may also be used as apurification General technique. Sodium salts of the compounds aresuccessfully recrystallized from nitromethane. I

EXAMPLE 2 Trifluoromethanesulfonamide (9.1 g., 0.06 mole), sodiumcarbonate (12.9 g., 0.12 mole) and acetone (250 ml.) are stirred forfour hours. 4-Cyanobenzoyl chloride (10.1 g., 0.061 mole) is added andthe solution is stirred overnight. The solution is filtered and theacetone is evaporated in vacuo. Water is added to dissolve the crudeproduct and the solution is filtered, then acidified to precipitate theproduct. The suspension is extracted with dichloromethane, the extractsare dried over magnesium sulfate, filtered, and the solvent is removedin vacuo. The product is purified by sublimation at 130 C./0.03 mm. toyield a white solid, N-4- I Found: 38.9

The following compounds are prepared from trifiuoromethane ortrifluoroethane sulfonamide and appropriately substituted aroyl halides,according to the procedure of Example 1.

Example Melting point No. Compound (in C.)

3 Nbenzoyltrifluoromethanesulfonamide 112.5-114.5 4N-(2-lluorobenzoyl)trifluoro methanesulfonamide 62-64 5N-(3-nitrobenzoyl)lrifluoromcthanesulfonamide 145-152 6 N-(3-trifluoromethylbenzoy1)- 1ri11uoromethanesulfonamide 148-1495 7 N-(."l-hromobenzoyl )trifluoromclhuncsulfonumide 134-135 8N-(3-ch1orubenzoyl)trifluoromelhunesullonamide 1 18-1 19.5 9N-(3-fluorobenzoyl)trifluoromethunesulfonamide 129.5-131 10N-(4-nitrobenzoy1)trifluoromethanesulfonamide 140-145 1 1N-(4-chlorobenzoyl)trifluoromethanesulfonamide 156.5-158 12N-(4-fluorobenzoyl )trifluoromethanesulfonamide 148-150 13 N-(3,4-dichlorobenzoyl)- trifluoromethanesulfonamide 167-1685 14 SodiumN-(2,4-dich10r0- benzoyl)trifluoromethanesulfonamide 218-220 (1. 15 N-(2-naphthoy1)trifluoromethanesulfonamide 149-151 1 N-(p-biphenylcarbonyl)trifluoro- 17 -178 methanesulfonamide 17N-(4-methoxybenzoyl)- lrifluorometh'anesulfonamide 1 12-1 14 18N-(3-methylbenzoyl)- lrifluoromethancsulfonamide 134-136 19N-benzoylperfluoroethanesulfonamide l15-117.5 20* TriethylammoniumN-(4-nitrobenzoyl)- trifluoromethanesulfonamide 101.5-105 21 SodiumN-(3nicotinyl)- trifluoromethanesulfonamide 361-364 d. 22 N-(2-thenoy1)trifluoromethanesulfonamide 128-130 23 N(2l"uroyl)-trifluoromethanesulfonamide 130- 1 3 1 .5 24 SodiumN-pyrazinecarbonyltrilluoromclhanesulfonamide 366-367 Prepared usingtriethylamine as base in place of sodium carbonate.

WHAT IS CLAIMED IS: 1. A compound of the group consisting of acidiccompounds of the formula phenyl or naphthyl and R, is perfluoroalkyl ofone or two carbon atoms; and pharmaceutically acceptable salts thereof.

2. A compound according to claim 1 wherein R, is

trifluo romethyl and AI is phenyl.

3. The compound sodium N-( 2 ,4-dichlorobenzoyl)trifluoromethanesulfonamide according to claim 1.

4. The compound N-( 3- chlorobenzoyl)trifluoromethanesulfonamideaccording to claim 1.

5 The compound N-( 4- chlorobenzoyl )trifluoromethanesulfonamideaccording to claim 1.

6. The compound N-( 3- bromobenzoyl)trifluoromethanesulfonamideaccording to claim 1.

7. The compound N-( 2- fluorobenzoyl)trifluoromethanesulfonamideaccording to claim 1.

8. The compound N-( 3- nitrobenzoyl)trifluoromethanesulfonamideaccording to claim 1.

9. The compound N-(3-trifluoromethylbenzoyl)trifluoromethane-sulfonamideaccording to claim 1.

10. The compound N-( 3- fluorobenzoyl)trifluoromethanesulfonamideaccording to claim 1.

11. The compound N-(4- nitrobenzoyl)trifluoromethanesulfonamideaccording to claim 1.

12. The compound N-(4- fluorobenzoyl)trifluoromethanesulfonamideaccording to claim 1.

13. The compound N-(4- cyanobenzoyl)trifluoromethanesulfonamideaccording to claim 1.

14. The compound N-(p-biphenylcarbony1)trifluoromethanesulfonamideaccording to claim 1.

15 The compound N-( 3 ,4- dichlorobenzoyl)trifluoromethanesulfonamideaccording to claim 1.

2. A compound according to claim 1 wherein Rf is trifluoromethyl and Aris phenyl.
 3. The compound sodiumN-(2,4-dichlorobenzoyl)trifluoromethanesulfonamide according to claim 1.4. The compound N-(3-chlorobenzoyl)trifluoromethanesulfonamide accordingto claim
 1. 5. The compoundN-(4-chlorobenzoyl)trifluoromethanesulfonamide according to claim
 1. 6.The compound N-(3-bromobenzoyl)trifluoromethanesulfonamide according toclaim
 1. 7. The compound N-(2-fluorobenzoyl)trifluoromethanesulfonamideaccording to claim
 1. 8. The compoundN-(3-nitrobenzoyl)trifluoromethanesulfonamide according to claim
 1. 9.The compound N-(3-trifluoromethylbenzoyl)trifluoromethane-sulfonamideaccording to claim
 1. 10. The compoundN-(3-fluorobenzoyl)trifluoromethanesulfonamide according to claim
 1. 11.The compound N-(4-nitrobenzoyl)trifluoromethanesulfonamide according toclaim
 1. 12. The compound N-(4-fluorobenzoyl)trifluoromethanesulfonamideaccording to claim
 1. 13. The compoundN-(4-cyanobenzoyl)trifluoromethanesulfonamide according to claim
 1. 14.The compound N-(p-biphenylcarbonyl)trifluoromethanesulfonamide accordingto claim
 15. The compoundN-(3,4-dichlorobenzoyl)trifluoromethanesulfonamide according to claim 1.